Bone marrow mesenchymal stem cells (BMMSCs) are multipotent stem cells capable of differentiating into different lineage cells including osteoblasts, chondrocytes, adipocytes, cardiomyocytes, myoblasts, and neural cells. A recent major breakthrough was the discovery that BMMSCs exert a profound inhibitory effect on T cells. While our preliminary studies revealed that activated T cells are capable of inducing BMMSC apoptosis through the Fas/FasL pathway, suggesting a novel crosstalk mechanism between T cells and BMMSCs. Immune diseases target the orofacial bones with specific phenotypes as seen in periodontal diseases, cherubism, and hyperparathyroid jaw tumor syndrome. Moreover, the orofacial jaw bones contain MSCs (OFMSCs) that are distinct to BMMSCs in terms of differentiation traits and tissue regeneration characteristics. Therefore, the objective of this application is to explore whether and how T cells regulate OFMSCs and whether this regulation contributes to orofacial bone disorders. Our preliminary studies identified that we are able to isolate and expand mouse OFMSCs, which allow us to use mouse models to study the interplay between OFMSCs and T cells. This achievement is critical for the proposed studies because isolation and expansion of mouse OFMSCs are difficult and reliant on stem cell culture experience. Our preliminary data showed that mouse OFMSCs differ from BMMSCs in inhibiting T cell activities in vitro. Our hypothesis is that T cells regulate OFMSCs in a way distinctive from those discovered in the interplays between T cells and BMMSCs, which may link to the orofacial bone phenotypes of immune diseases. In this application, we will explore how T cells interplay with OFMSCs using BMMSCs as a comparison. Moreover, we will examine whether T cell-mediated OFMSC response involved in orofacial phenotypes of immune diseases such as T cell over-activated osteoporosis induced by ovarioectomy. Finally, we will assess whether systemic OFMSC infusion can offer therapeutic effect on T cell over-activated disorders. In summary, novel findings from our proposed studies will provide cellular and molecular basis for understanding interplays between T cells and OFMSCs. These data are likely to lead to new knowledge on identifying mechanisms of immune disorders associated with the orofacial bones. Project Narrative: The purpose of this study is to understand crosstalk between orofacial mesenchymal stem cells and immune cells and delineate the mechanisms by which the crosstalk may associate with orofacial bone diseases. We will use this knowledge to explore new approaches for orofacial bone disease treatment.